Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests
Authors: Kendra Vehik, David Boulware, Michael Killian, Marian Rewers, Richard McIndoe, Jorma Toppari, Åke Lernmark, Beena Akolkar, Anette-G. Ziegler, Henry Rodriguez, Desmond A. Schatz, Jeffrey P. Krischer, William Hagopian, Marian Rewers, Aaron Barbour, Kimberly Bautista, Judith Baxter, Daniel Felipe-Morales, Brigitte I. Frohnert, Marisa Stahl, Patricia Gesualdo, Michelle Hoffman, Rachel Karban, Edwin Liu, Alondra Munoz, Jill Norris, Holly O’Donnell, Stesha Peacock, Hanan Shorrosh, Andrea Steck, Megan Stern, Kathleen Waugh, Jorma Toppari, Olli G. Simell, Annika Adamsson, Sanna-Mari Aaltonen, Suvi Ahonen, Mari Åkerlund, Leena Hakola, Anne Hekkala, Henna Holappa, Heikki Hyöty, Anni Ikonen, Jorma Ilonen, Sanna Jokipuu, Leena Karlsson, Jukka Kero, Jaakko J. Koskenniemi, Miia Kähönen, Mikael Knip, Minna-Liisa Koivikko, Katja Kokkonen, Merja Koskinen, Mirva Koreasalo, Kalle Kurppa, Salla Kuusela, Jarita Kytölä, Jutta Laiho, Tiina Latva-aho, Laura Leppänen, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija Miettinen, Katja Multasuo, Teija Mykkänen, Tiina Niininen, Sari Niinistö, Mia Nyblom, Sami Oikarinen, Paula Ollikainen, Zhian Othmani, Sirpa Pohjola, Jenna Rautanen, Anne Riikonen, Minna Romo, Satu Simell, Päivi Tossavainen, Mari Vähä-Mäkilä, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Suvi M. Virtanen, Jin-Xiong She, Desmond Schatz, Diane Hopkins, Leigh Steed, Jennifer Bryant, Katherine Silvis, Michael Haller, Melissa Gardiner, Richard McIndoe, Ashok Sharma, StephenW. Anderson, Laura Jacobsen, John Marks, P.D. Towe, Anette G. Ziegler, Ezio Bonifacio, Cigdem Gezginci, Anja Heublein, Eva Hohoff, Sandra Hummel, Annette Knopff, Charlotte Koch, Sibylle Koletzko, Claudia Ramminger, Roswith Roth, Jennifer Schmidt, Marlon Scholz, Joanna Stock, Katharina Warncke, Lorena Wendel, Christiane Winkler, Åke Lernmark, Daniel Agardh, Carin Andrén Aronsson, Rasmus Bennet, Corrado Cilio, Susanne Dahlberg, Ulla Fält, Malin Goldman Tsubarah, Emelie Ericson-Hallström, Lina Fransson, Thomas Gard, Emina Halilovic, Gunilla Holmén, Susanne Hyberg, Berglind Jonsdottir, Naghmeh Karimi, Helena Elding Larsson, Marielle Lindström, Markus Lundgren, Marlena Maziarz, Maria Månsson Martinez, Jessica Melin, Zeliha Mestan, Caroline Nilsson, Yohanna Nordh, Kobra Rahmati, Anita Ramelius, Falastin Salami, Anette Sjöberg, Carina Törn, Ulrika Ulvenhag, Terese Wiktorsson, Åsa Wimar, William A. Hagopian, Michael Killian, Claire Cowen Crouch, Jennifer Skidmore, Luka-Sophia Bowen, Mikeil Metcalf, Arlene Meyer, Jocelyn Meyer, Denise Mulenga, Nole Powell, Jared Radtke, Shreya Roy, Davey Schmitt, Preston Tucker, Dorothy Becker, Margaret Franciscus, MaryEllen Dalmagro-EliasSmith, Ashi Daftary, Mary Beth Klein, Chrystal Yates, Jeffrey P. Krischer, Rajesh Adusumali, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Brant Burkhardt, Martha Butterworth, Nicholas Cadigan, Joanna Clasen, Kevin Counts, Laura Gandolfo, Jennifer Garmeson, Veena Gowda, Christina Karges, Shu Liu, Xiang Liu, Kristian Lynch, Jamie Malloy, Lazarus Mramba, Cristina McCarthy, Jose Moreno, Hemang M. Parikh, Cassandra Remedios, Chris Shaffer, Susan Smith, Noah Sulman, Roy Tamura, Dena Tewey, Michael Toth, Ulla Uusitalo, Kendra Vehik, Ponni Vijayakandipan, Melissa Wroble, Jimin Yang, Kenneth Young, Michael Abbondondolo, Lori Ballard, Rasheedah Brown, David Cuthbertson, Stephen Dankyi, Christopher Eberhard, Steven Fiske, David Hadley, Kathleen Heyman, Belinda Hsiao, Francisco Perez Laras, Hye-Seung Lee, Qian Li, Colleen Maguire, Wendy McLeod, Aubrie Merrell, Steven Meulemans, Ryan Quigley, Laura Smith, Beena Akolkar, Thomas Au, Todd Brusko, Suzanne Bennett Johnson, Eoin McKinney, Tomi Pastinen, Eric Triplett
Journal: Diabetes Care (2022)

Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies.Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190).A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7-18.6, P < 0.0001) and TrialNet (HR 5.09, 95% CI 3.3-7.9, P < 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82).An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies.